Edoxaban in the Evolving Scenario of Non Vitamin K Antagonist Oral Anticoagulants Imputed Placebo Analysis and Multiple Treatment Comparisons
Reboldi G (2014) Edoxaban in the Evolving Scenario of Non Vitamin K Antagonist Oral Anticoagulants Imputed Placebo
Analysis and Multiple Treatment Comparisons. PLoS ONE 9(6): e100478. doi:10.1371/journal.pone.0100478
Edoxaban in the Evolving Scenario of Non Vitamin K Antagonist Oral Anticoagulants Imputed Placebo Analysis and Multiple Treatment Comparisons
Paolo Verdecchia 0
Fabio Angeli 0
Gregory Y. H. Lip 0
Gianpaolo Reboldi 0
Adrian V. Hernandez, Universidad Peruana de Ciencias Aplicadas (UPC), Peru
0 1 Department of Medicine, Hospital of Assisi , Assisi, Italy, 2 Cardiology and Cardiovascular Pathophysiology , University Hospital of Perugia , Perugia , Italy , 3 University of Birmingham Centre for Cardiovascular Sciences, City Hospital , Birmingham , United Kingdom , 4 Department of Medicine, University of Perugia , Perugia , Italy
Background: Edoxaban recently proved non-inferior to warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation (AF). We conducted an imputed-placebo analysis with estimates of the proportion of warfarin effect preserved by each non vitamin K antagonist oral anticoagulant (NOAC) and indirect comparisons between edoxaban and different NOACs. Methods and Findings: We performed a literature search (up to January 2014), clinical trials registers, conference proceedings, and websites of regulatory agencies. We selected non-inferiority randomised controlled phase III trials of dabigatran, rivaroxaban, apixaban and edoxaban compared with adjusted-dose warfarin in non-valvular AF. Compared to imputed placebo, all NOACs reduced the risk of stroke (ORs between 0.24 and 0.42, all p,0.001) and all-cause mortality (ORs between 0.55 and 0.59, all p,0.05). Edoxaban 30 mg and 60 mg preserved 87% and 112%, respectively, of the protective effect of warfarin on stroke, and 133% and 121%, respectively, of the protective effect of warfarin on all-cause mortality. The risk of primary outcome (stroke/systemic embolism), all strokes and ischemic strokes was significantly higher with edoxaban 30 mg than dabigatran 150 mg and apixaban. There were no significant differences between edoxaban 60 mg and other NOACs for all efficacy outcomes except stroke, which was higher with edoxaban 60 mg than dabigatran 150 mg. The risk of major bleedings was lower with edoxaban 30 mg than any other NOAC, odds ratios (ORs) ranging between 0.45 and 0.67 (all p,0.001). Conclusions: This study suggests that all NOACs preserve a substantial or even larger proportion of the protective warfarin effect on stroke and all-cause mortality. Edoxaban 30 mg is associated with a definitely lower risk of major bleedings than other NOACs. This is counterbalanced by a lower efficacy in the prevention of thromboembolism, although with a final benefit on all-cause mortality.
. These authors contributed equally to this work.
Vitamin K antagonists (VKA) have long been the only oral
anticoagulant agents available for effective thromboprophylaxis in
patients with atrial fibrillation (AF). In a landmark meta-analysis of
trials conducted in AF patients randomized to either adjusted-dose
warfarin versus placebo or control for a mean exposure time of 1.6
years per patient, warfarin reduced the risk of stroke by 64% (95%
confidence interval (CI): 49% to 74%), and that of ischemic stroke
by 67% (CI: 54% to 77%), as well as a reduction in all-cause
mortality by 26% (CI 3% to 43%) .
This impressive benefit made it unethical to compare any non
vitamin K antagonist oral anticoagulant (NOAC)  with placebo
in subsequent outcome trials. Consequently, the major studies
published over the past few years with the direct thrombin
inhibitor dabigatran  and the factor Xa inhibitors rivaroxaban
, apixaban  and, lastly, edoxaban , were well-designed
non-inferiority trials of each single NOAC versus adjusted-dose
warfarin. Notably, any inference about the efficacy of NOACs
from these studies assumes that the benefit of warfarin in
preventing stroke and systemic embolism approaches that found
in prior trials vs placebo or control, as summarized in the above
mentioned meta-analysis .
After these studies, dabigatran, rivaroxaban and apixaban
gained regulatory approval in many countries for prevention of
stroke in patients with non valvular AF. The dose of dabigatran
110 mg b.i.d. has not been approved in the Unites States by the
Food and Drug Administration (FDA), that approved the 75 mg
b.i.d. dose in patients with glomerular filtration rate between 15
and 29 ml/min .
Although these drugs are valuable alternative to warfarin [8,9],
the physician has few arguments to direct his/her choice to one
over the other in the absence of direct head-to-head comparisons.
Several indirect comparisons have been conducted between
dabigatran, rivaroxaban and apixaban . In the context
of limitations of indirect comparisons [16,17], these analyses
suggest a lower risk of stroke/systemic embolism with dabigatran
150 mg bid versus dabigatran 110 mg bid and rivaroxaban, and a
lower risk of major bleedings with dabigatran 110 mg bid and
apixaban versus dabigatran 150 mg bid and rivaroxaban [18,19].
More recently, edoxaban emerged as the fourth NOAC in its
class. In the Effective Anticoagulation with Factor Xa Next Generation in
Atrial FibrillationThrombolysis in Myocardial Infarction 48 (ENGAGE
AF-TIMI 48) trial, 21,105 patients with non valvular AF were
randomized to adjusted-dose warfarin or two doses (30 mg q.d.,
60 mg q.d.) of edoxaban . The primary efficacy endpoint was a
composite of stroke and systemic embolism and the main safety
end-point was major bleeding . Both doses of edoxaban were
non inferior to warfarin for the prevention of stroke and systemic
embolism . Thus far, edoxaban has not yet gained approval by
FDA and other regulatory Agencies.
The ENGAGE-AF trial  expanded the horizon of available
alternatives to VKA and offered the opportunity of a more
comprehensive evaluation of this class of drugs. In the light of this
new trial, the present study has three goals: (1) to estimate the
proportion of warfarin effect preserved by each of the NOACs and
their efficacy versus a putative placebo on the risk of stroke and
allcause mortality; (2) to update the previous estimates of benefits and
harms of NOACs as a whole versus warfarin; (3) to estimate,
through indirect comparisons, the relative efficacy and safety of
either dose of edoxaban versus different NOACs.
We used the PRISMA (Preferred Reporting Items for
Systematic reviews and Meta-Analyses) statement for reporting systematic
reviews and meta-analyses of randomized controlled trials (RCTs)
Randomized patients, N
ROCKET AF Rivaroxaban
ENGAGE AF Edoxaban
44 (951 Centers)
45 (1178 Centers)
D 110 mg b.i.d.: N = 6,015 R 20 mg q.d.: N = 7,131
Warfarin: N = 7,133
39 (1034 Centers)
A 5 mg q.d.: N = 9,120
Warfarin: N = 9,081
Open label vs. warfarin
D 150 mg b.i.d.: N = 6,076
Warfarin: N = 6,022
Patients lost to follow-up
Median duration of follow-up, years
Creatinine clearance #50 ml/min
Paroxysmal AF, %
Prior stroke, TIA or systemic
Heart failure, %
Diabetes mellitus, %
Drugs at baseline
Vitamin K antagonist, %
Average TTR in the warfarin group
46 (1393 Centers)
E 30 mg q.d.: N = 7,034
E 60 mg q.d.: N = 7,035
Warfarin: N = 7,036
as a guide for this study (PRISMA checklist S1) , including the
preparation of a protocol and analysis plan (Protocol S2).
Following a literature search (up to January 2014), to perform
indirect comparisons and imputed placebo analyses in the
noninferiority setting, we identified four large phase III studies
(Figure 1): Randomized Evaluation of Long-Term Anticoagulation Therapy
(RE-LY) , Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition
Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism
Trial in Atrial Fibrillation (ROCKET-AF) , Apixaban for Reduction in
Stroke and Other Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) , and ENGAGE AF-TIMI 48  (see table 1 for the
complete summary of trialscharacteristics). For RE-LY , we
integrated the original data with the update published in 2010
. As shown in figure 1, we excluded systematic overviews or
studies with different anticoagulants (n = 4748), non comparative
studies (n = 111), studies without warfarin control (n = 48) and
other 32 studies for a variety of reasons reported in the table. We
included only active control phase III non-inferiority studies
because our aim was to provide estimates of the proportion of
warfarin effect preserved by NOACs and their efficacy versus an
imputed placebo as a measure of assay sensitivity. Active
controlled trials might be uninformative as they can neither
demonstrate the effectiveness of a new agent nor provide a valid
comparison to control therapy unless assay sensitivity can be
We extracted data on both efficacy and safety outcomes as
detailed below and in the study protocol (Protocol S2). Additional
data on outcomes, not available in the main papers of included
studies, were retrieved from the FDA website (http://www.fda.
The authors of this study independently extracted all outcome
data using a pre-specified form and disagreements were resolved
Data synthesis and statistical analysis
Efficacy outcomes included the composite of stroke and systemic
embolism (i.e., the primary efficacy outcome event in each of the
four trials ), stroke (i.e., all strokes), hemorrhagic stroke,
ischemic or uncertain type of stroke and systemic embolism. For
safety, we considered major bleeding, intracranial bleeding,
gastrointestinal bleeding, myocardial infarction and all-cause
In keeping with previous studies [10,18] the expected effect of
NOACs as a class versus warfarin, was calculated as a weighted
average using the inverse of the variance of the log(odds ratio
(OR)) as weights. For this analysis, the higher doses of dabigatran
(150 mg b.i.d. arm of RE-LY ) and edoxaban (60 mg q.d. arm
of ENGAGE AF-TIMI 48 ) were analyzed with data from
ROCKET-AF  and ARISTOTLE . In a separate analysis,
we analyzed the lower doses of dabigatran (110 mg b.i.d. arm of
RE-LY ) and edoxaban (30 mg q.d. arm of ENGAGE
AFTIMI 48 ) with data from the other two trials.
We used the methodology introduced by Hasselblad and Kong
to estimate the effects of NOACs versus imputed placebo .
Such approach assumes that previous trials tested warfarin versus
placebo using the same outcome event as in the trials of NOACs
versus warfarin, and that the populations exposed to trials of
warfarin vs placebo and warfarin versus NOACs are similar .
The imputed placebo approach also relies on the assumption of
constancy of the beneficial effect of warfarin versus placebo as
observed in previous controlled trials . This last assumption,
however, is conditioned by the differences in patient
characteristics, concomitant medications, intensity of treatment, and other
trial design features [22,24,26,27]. In addition, stroke rate seems to
be declining over time both in the general population  and in
AF patients treated with warfarin . An effective way to
discount for this limitation is to estimate the proportion of the
warfarin treatment effect retained by each NOAC [25,30,31].
This is accomplished by determining the ratio of the effect of the
new treatment versus putative placebo relative to the effect of the
standard treatment versus placebo along with its estimated
variance and CI [22,24,26,27]. To prevent further limitations
due to the use of a composite outcome (stroke and systemic
embolism) in new trials as opposed to older ones, we restricted the
imputed placebo analysis to stroke and all-cause mortality, as
unequivocal and comparable outcome events in the trials of
warfarin vs. placebo [1,32] and NOACs versus warfarin . For
this purpose, the warfarin treatment effect was derived from a
random-effects meta-analysis of 6 historical placebo-controlled
trials  using the OR as the analysis metric.
We made multiple treatment comparisons between edoxaban
and other NOACs using the Bucher method [39,40] with warfarin
used as common comparator. Because of the limited number of
trials and in the absence of head-to-head comparisons between
different NOACs, we did not make a formal network or mixed
treatment comparison meta-analysis, in line with the
recommendations and caveats outlined by the International Society for
Pharmacoeconomics and Outcomes Research [41,42]. In brief, we
estimated the OR of an event with a given NOAC (NOAC1)
versus another NOAC (NOAC2) (ORNOAC1/NOAC2) by dividing
the OR of NOAC1 versus warfarin (ORNOAC1/warfarin) by the OR
of NOAC2 versus warfarin (ORNOAC2/warfarin). We estimated the
OR of selected events for each dose of edoxaban versus dabigatran
(each dose), rivaroxaban and apixaban. The Bucher method
assumes that the differences between a given NOAC and warfarin
in terms of efficacy and safety would have been analogous if tested
in different trial populations exposed to different NOACs versus
warfarin . However, since different studies were not fully
comparable for some features including the thromboembolic risk,
reflected by the CHADS2 score, the time in therapeutic range and
other methodological aspects (open-label versus double-blind),
indirect comparisons should be interpreted prudently [16,17].
We used the R software version 3 (R Foundation for Statistical
Computing, Vienna, Austria. URL http://www.R-project.org) for
the analyses, with pre-specified efficacy and safety outcomes.
In aggregate, the four trials  accrued 71,683 patients.
Table 1 shows the main features of the four studies . The
sample size was larger (N = 21,105), and the median duration of
follow-up longer (2.8 years) in the ENGAGE AF-TIMI 48  than
in the other studies. Similar to ROCKET-AF  and
ARISTOTLE , ENGAGE AF-TIMI 48  was a double-blind trial
vs warfarin , whereas RE-LY  was an open-label study of
dabigatran versus warfarin with a double-blind comparison
between the two different dabigatran doses . Based on the
CHADS2 score , the risk of stroke in the ENGAGE AF-TIMI
48 trial  was intermediate (2.8 points) between ROCKET-AF
 (3.5 points) on a side, and RE-LY  (2.2 points) and
ARISTOTLE  (2.1 points) on the other side. In terms of
prevalence of heart failure, diabetes and hypertension at baseline,
the ENGAGE AF-TIMI 48 was more similar to ROCKET-AF
 than to the other two studies. The average time in therapeutic
range was 64.9% (median time 68%) in ENGAGE AF-TIMI 48
, as opposed to 64% in RE-LY , 55% in ROCKET AF 
and 62% in ARISTOTLE .
.0041 .0166 ,.0001 .0021 .0225 ,.0001 ,.0001 .0688 .6040 ,.0001
.9609 .2710 .4005 .0512 .8311 .3807 .3904 .5511 .7811 .4809
.0083 .5508 .6403 .1108 .7058 .7066 .4035 .0109 .4009 .4408
.0990 .0973 .0433 .1128 .0811 .0727 .0412 .1052 .1023 .0849
,.0001 ,.0001 ,.0010 .3201 .0600 ,.0001 ,.0001 ,.0001 .3104 .1000
.6084 .8081 .1065 .2103 .3608 .0109 .6605 .4014 .8210 .5809
.0751 .0782 .0420 .0825 .0417 .0791 .0405 .1105 .0862 .0835
Weighted average effect versus warfarin
When the higher doses of dabigatran and edoxaban were used
for the estimates versus warfarin (Table 2, left side), NOACs as a
whole reduced the risk of stroke/systemic embolism (by 21%; p,
0.001), stroke (by 20%; p,0.001), hemorrhagic stroke (by 50%;
p,0.001) and systemic embolism (by 40%; p = 0.006). On the
safety side, NOACs reduced the risk of major bleedings (by 15%;
p,0.001), intracranial bleedings (by 52%; p,0.001) and death
from any cause (by 10%; p = 0.001). Ischemic (or uncertain) stroke
and myocardial infarction did not differ significantly between
NOACs and warfarin, whereas gastrointestinal bleeding were
more common with NOACS than with warfarin (by 29%; p,
0.001).When using the lower doses of dabigatran and edoxaban
(Table 2, right side), NOACs reduced stroke/systemic embolism
(by 9%; p = 0.041) and hemorrhagic stroke (by 37%; p,0.001). All
strokes (p = 0.166) and systemic embolism (p = 0.225) did not
differ, while the ischemic (or uncertain) type of stroke was more
frequent with NOACs than with warfarin (by 13%; p = 0.021). On
the safety side, NOACs reduced the risk of major bleedings (by
27%; p,0.001), intracranial bleedings (by 59%; p,0.001) and
allcause death (by 91%; p,0.001), whereas gastrointestinal bleedings
(p = 0.688) and myocardial infarction (p = 0.640) did not differ
between NOACs and warfarin.
Imputed placebo analysis and proportion of warfarin
The comparison of each NOAC versus an imputed placebo on
the risk of stroke is shown in figure 2. All NOACs effectively
reduced the risk of stroke (all p,0.001). OR ranged between 0.236
for dabigatran 150 mg, and 0.417 for edoxaban 30 mg.
All NOACs reduced the risk of all-cause mortality (figure 3) to a
similar extent, with ORs ranging between 0.552 and 0.591 (all p,
0.05). Overall, risk reductions were somewhat larger with NOACs
than with warfarin (OR 0.639, 95% CI: 0.414 to 0.987, p = 0.044)
but not formally significant.
The estimated proportion of warfarin benefit retained on stroke
is shown in figure 4. In increasing order, edoxaban 30 mg
preserved 87% (95% CI 71103) of the protective effect of
warfarin, followed by dabigatran 110 mg (108%; 95% CI: 87
129), edoxaban 60 mg (112%; 95% CI: 96129), rivaroxaban
(119%; 95% CI: 98139), apixaban (124%; 95% CI: 103144)
and dabigatran 150 mg (143%; 95% CI: 116170). The estimated
proportion of warfarin benefit retained on all-cause mortality is
shown in figure 5. In increasing order, rivaroxaban preserved
118% (95% CI 87148) of the protective effect of warfarin,
followed by dabigatran 110 mg (121%; 95% CI: 85157),
edoxaban 60 mg (121%; 95% CI: 90151), apixaban (126%;
95% CI: 90162), dabigatran 150 mg (128%; 95% CI: 87168)
and edoxaban 30 mg (133%; 95% CI 93172).
Adjusted indirect comparisons between edoxaban and
OR and 95% CI are reported in tables 3 (efficacy outcomes)
and 4 (safety outcomes). The risk of stroke/systemic embolism was
significantly higher with edoxaban 30 mg than with dabigatran
150 mg orapixaban. The risk of total stroke and ischemic (or
uncertain) stroke was also significantly higher with edoxaban
30 mg than with dabigatran 150 mg, rivaroxaban or apixaban.
Apart from systemic embolism and myocardial infarction, which
were higher with edoxaban 30 mg than with rivaroxaban, none of
the other outcomes showed statistically significant differences
between edoxaban 30 mg and any other NOAC. There were no
significant differences between the higher dose of edoxaban
(60 mg) and any other NOAC in the efficacy outcomes, apart from
a slightly higher risk of stroke with edoxaban than rivaroxaban
(p = 0.032). The risk of all-cause death did not differ between
either dose of edoxaban and other NOACs. The risk of major
bleedings (table 4) was significantly lower with edoxaban 30 mg
than any other NOAC, and that of gastrointestinal bleedings was
lower with edoxaban 30 mg compared with rivaroxaban and both
doses of dabigatran. The risk of intracranial bleeding was lower
with edoxaban 30 mg versus rivaroxaban. The higher dose of
edoxaban did not differ significantly from any other NOAC in
terms of safety outcomes, apart from a lower risk of major bleeding
compared to rivaroxaban and higher risk of gastrointestinal
bleedings compared to apixaban.
The main novel finding of the present study is the estimate,
obtained through an imputed placebo analysis, of the proportion
of warfarin effect preserved by all NOACs on stroke and all-cause
mortality in patients with non valvular AF. We based our estimate
on a landmark meta-analysis of randomized trials that compared
adjusted-dose warfarin versus placebo  and four pivotal
noninferiority trials in which 71,683 patients were randomized to
adjusted-dose warfarin or NOACs .
Imputed placebo analysis
This kind of analysis is increasingly performed to estimate how
might be the effect of a new treatment if compared versus placebo
in the case that a placebo-controlled trial with the new agent
would be unethical or unfeasible. Although there is always concern
about the value of historic control data, imputed placebo analyses
are required by drug regulatory Agencies. For example, the Food
and Drug Administration (FDA) approved the use of enoxaparin
in the treatment of acute coronary syndrome on the basis of an
imputed placebo analysis that included a meta-analysis of
randomized trials of unfractionated heparin plus aspirin versus
aspirin alone , and one randomized comparison of enoxaparin
versus unfractionated heparin . Crucial for FDA approval was
the demonstration of the high probability that enoxaparin retained
at least 80% of the therapeutic effect of unfractionated heparin
In the case of NOACs, placebo controlled trials in patients with
non valvular AF would be unethical because warfarin is highly
effective in preventing stroke in these patients . When
conducting an imputed placebo analysis, two main conditions
are required: (a) there is unequivocal historical evidence, that may
or may not be obtained through a meta-analysis, of the
comparators superior efficacy versus placebo; (b) the patients
enrolled in the trials of active comparator versus placebo and new
treatment versus active comparator share common clinical
In the present analysis, all NOACs significantly lowered the risk
of stroke versus imputed placebo, with reductions ranging between
71% with the higher dose of dabigatran and 38% with the lower
dose of edoxaban (all p,0.001). Consequently, all NOACs
retained more that 100% of the benefit of warfarin with the
exception of edoxaban 30% that, however, retained 87% of its
benefit. The higher dose of dabigatran, apixaban and the lower
dose of edoxaban were the sole NOACs that significantly reduces
all-cause mortality versus imputed placebo.
Our findings confirmed the results of a recent meta-analysis 
in showing that NOACs, as a whole, are superior to warfarin in
reducing the primary composite outcome of stroke/systemic
embolism and the secondary outcomes of death and hemorrhagic
stroke. While intracranial bleedings were less frequent with
NOACs than warfarin, gastrointestinal bleedings were more
frequent with NOACs, but only with the higher dose regimens.
In the present analysis we focused on edoxaban as the latest
entry in the available scenario of NOACs. In the ENGAGE-AF
TIMI 48 trial , edoxaban 30 mg was non-inferior to
adjusted dose warfarin on the primary composite outcome of
stroke/systemic embolism and reduced by 13% the risk of
allcause death (p = 0.006) and by 15% the risk of cardiovascular
death (p = 0.008). Also, the composite of death or disabling
stroke was by 10% lower (p = 0.02) with edoxaban 30 mg than
it was with warfarin. In the ENGAGE AF-TIMI 48 trial,
edoxaban 30 mg was also associated with a 53% lower risk of
major bleeding, and a 33% lower risk of gastrointestinal
bleedings versus warfarin.
e n k 9 61 .00 66 783 .00 5 72 .00 3 87 .00
Isch rou trso .217 .(90 p= .81 .(1 ,p .551 .(11 =p .561 .(11 =p .9830 .(6660 .04p= .0341 .(9550 .00p= .8061 .(8120 .05p= .9101 .(8220 .05p=
eHm .0176 .(5014 .08p= .2581 .(5880 .05p= .5710 .(3080 .00p= .6500 .(370 .01p= .7471 .(8720 .01p= .6002 .(9950 .00p= .3590 .(5250 .08p= .6501 .(3460 .08p=
ek .)1609 90 .2334 10 .1773 21 .1851 30 .)2418 93 .1811 .320 .)3716 73 .)3471 67
ran ibd ran ibd ban d n id n id an
itga gm itga gm rxoaa gqm xaabn gdq itrgaa gbm itraga gbm rxoaba gqdm xaban dqg
Edoxaban 30 mg vs. Dabigatran 110 mg bid
0.581 (0.470.719) p,0.001
1.033 (0.5921.803) p = 0.909
Edoxaban 60 mg vs. Dabigatran 110 mg bid
0.979 (0.8021.194) p = 0.831
0.498 (0.4040.614) p,0.001
0.740 (0.4411.243) p = 0.255
0.465 (0.3340.649) p,0.001
0.454 (0.3680.56) p,0.001
0.47 (0.2880.767) p = 0.003
0.421 (0.3080.575) p,0.001
0.672 (0.5440.829) p,0.001
0.729 (0.4511.177) p = 0.196
1.539 (0.9072.611) p = 0.11
0.839 (0.6911.02) p = 0.078
0.764 (0.6280.93) p = 0.007
0.700 (0.4431.107) p = 0.127
0.768 (0.5751.026) p = 0.074
1.131 (0.9291.377) p = 0.22
1.086 (0.6951.697) p = 0.718
Dabigatran 150 mg bid
Rivaroxaban 20 mg qd
Apixaban 5 mg qd
Dabigatran 150 mg bid
Rivaroxaban 20 mg qd
Apixaban 5 mg qd
Safety end-points. Significant comparisons are printed in bold.
Skjth and coworkers recently published an indirect comparison
analysis between different NOACs, including edoxaban . Such
analysis, however, did not estimate the benefits of each agent
versus imputed placebo and the proportion of the warfarin effect
preserved. The present study and that by Skjth and coworkers
share the conclusion that edoxaban 60 mg is comparable to
apixaban, rivaroxaban and the lower dose of dabigatran, but
inferior to the higher dose of dabigatran, for prevention of
stroke. In terms of bleeding end-points, the higher dose of
edoxaban is comparable to both doses of dabigatran, and
associated with less major bleedings than rivaroxaban and more
gastrointestinal bleedings than apixaban . Conversely, the
lower dose of edoxaban is comparable to the lower dose of
dabigatran, but inferior to all other NOACs for prevention of
stroke. The poorer efficacy of the lower dose of edoxaban
appears to be outweighed by a higher safety, as reflected by a
less risk of major bleedings versus all other NOACs and a less
risk of gastrointestinal bleedings versus rivaroxaban and both
doses of dabigatran.
Our study extends the conclusions by Skjth and coworkers in
showing that, despite its less antithrombotic efficacy, the lower
dose of edoxaban significantly reduces the risk of any stroke (by
58%) and all-cause mortality (by 30%) when compared with a
putative placebo. At the point estimate, the lower dose of
edoxaban preserved 87% of the benefit of warfarin on stroke
and 133% of the benefit of warfarin on all-cause mortality.
Notably, the 95% CI of the estimated proportion of the warfarin
benefit on stroke preserved by edoxaban 30 mg ranged between
69% in the worst case (i.e., the lower limit of the 95% CI) and
103% in the best case (i.e., the upper limit of the 95% CI). For
allcause mortality, it ranged between 93% in the worst case and
172% in the best case.
The preservation of a pre-specified fraction of the benefit of the
control drug by the test drug is a concept that is applied routinely
in non-inferiority trials . FDA suggests that non-inferiority
trials can be considered statistically persuasive when the test drug
preserves at least 60% of the effect of the control treatment .
Thus, both doses of edoxaban were significantly more effective
than imputed placebo in reducing the risk of stroke and preserved
a substantial proportion of the benefit of warfarin, in line with the
FDA guidance .
0.768 (0.5431.087) p = 0.137
1.142 (0.8241.581) p = 0.426
0.849 (0.6211.16) p = 0.303
Limitations of the study
The indirect comparison analysis is used to estimate efficacy or
safety differences between treatments in the absence of direct
head-to-head comparisons [39,40]. It is unlikely that direct
comparisons between different NOACs will be ever undertaken.
However, the indirect comparison analysis has well recognized
inherent limitations [16,17]. It assumes that the differences tested
in the analysis between any NOAC and the common comparator
(warfarin in our case) would have been similar (similarity
assumption) also in the context of a different trial population
exposed to a different NOAC. The stability of relative treatment
effects across trials would make warfarin a credible common
comparator. The methods assumes, for example, that the efficacy
and safety differences between dabigatran and warfarin found in
the RE-LY  study would have been the same in the context of
the patient population and trial methodology of ROCKET AF 
or ENGAGE-AF TIMI 48 . By contrast, some differences exist
between the four major trials versus warfarin  that could limit
the validity of the similarity assumption by making unclear
whether the different effects versus warfarin would be
attributable to the NOAC alone. Of utmost importance, the
risk of thromboembolic complications, reflected by the
CHADS2 score, was higher in the ROCKET AF  and
ENGAGE AF-TIMI 48  than in the other trials (table 1).
However, none of the subgroups analyses of any NOAC versus
warfarin on the primary outcome was statistically significant
for interaction by CHADS2 score . Other confounding
factors that may limit the validity of indirect comparison
analysis in our setting include the open (RE-LY ) versus
double blind (other trials) design of warfarin administration,
the average time in therapeutic range and the concomitant use
of aspirin and other drugs.
In the present study, we tried to put the results of ENGAGE
AFTIMI 48 trial  in the scenario of available outcome data on
NOACs. Notwithstanding the known caveats of indirect
comparisons, while the higher dose of edoxaban did not show important
differences from other NOACs in terms of efficacy and safety, the
30 mg dose showed some distinctive features. The better safety
profile in terms of major bleedings compared to all other NOACs,
and of gastrointestinal bleedings compared to dabigatran and
rivaroxaban, would make the lower dose of edoxaban a reasonable
option in patients with high or very high risk of bleeding . The
lower relative antithrombotic efficacy versus all other NOACs,
except the lower dose of dabigatran, should be considered in the
light of two findings: 1) the reduction of all-cause mortality in the
head-to-head comparison versus warfarin; 2) the significant
protective effect on stroke and all-cause mortality in the
imputed-placebo analysis and the preservation of a substantial
proportion of the protective benefit of warfarin on both outcome
PRISMA Checklist S1 PRISMA (Preferred Reporting Items for
Systematic reviews and Meta-Analyses) statement for reporting
systematic reviews and meta-analyses.
Protocol and analysis plan.
Conceived and designed the experiments: PV FA GYHL GR. Analyzed
the data: PV FA GYHL GR. Contributed reagents/materials/analysis
tools: PV FA GYHL GR. Wrote the paper: PV FA GYHL GR.
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